Abstract

Mounting evidence underlines the role of inducible nitric oxide synthase
(iNOS) in hepatocellular carcinoma (HCC) development,but its functional
interactions with pathways involved in HCC progression remain
uninvestigated. We analyzed in preneoplastic and neoplastic livers from
Fisher 344 and Brown Norway rats, possessing different genetic
predisposition to HCC and in human HCC iNOS function and interactions
with nuclear factor-kB (NF-kB) and Ha-RAS/extracellular signal-regulated
kinase (ERK) during hepatocarcinogenesis; influence of genetic
predisposition to liver cancer on these pathways. We found progressive iNos
induction in rat at higher levels in the most aggressive rats. iNOS, inhibitor of
kB kinase/NF-kB and RAS/ERK upregulation was significantly higher in
HCC with poorer prognosis, positively correlated with tumor proliferation,
genomic instability and microvascularization and negatively with apoptosis.
Suppression of iNOS signaling led to decreased HCC growth and NF-kB and
RAS/ERK expression and increased apoptosis both in vivo and in vitro.
Conversely, block of NF-kB signaling or ERK signaling caused iNOS
downregulation in HCC cell lines. These findings indicate that iNOS cross
talk with NFkB and Ha-RAS/ERK cascades influences HCC growth and
prognosis, suggesting that key component of iNOS signaling could represent
important therapeutic targets for human HCC.